EP1169030A1 - Agents et procedes permettant de favoriser des gains de production animale - Google Patents

Agents et procedes permettant de favoriser des gains de production animale

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Publication number
EP1169030A1
EP1169030A1 EP00911506A EP00911506A EP1169030A1 EP 1169030 A1 EP1169030 A1 EP 1169030A1 EP 00911506 A EP00911506 A EP 00911506A EP 00911506 A EP00911506 A EP 00911506A EP 1169030 A1 EP1169030 A1 EP 1169030A1
Authority
EP
European Patent Office
Prior art keywords
agent
composition according
animal
agents
antistress
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00911506A
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German (de)
English (en)
Other versions
EP1169030A4 (fr
Inventor
Christian John Cook
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Horticulture and Food Research Institute of New Zealand Ltd
Original Assignee
Horticulture and Food Research Institute of New Zealand Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Horticulture and Food Research Institute of New Zealand Ltd filed Critical Horticulture and Food Research Institute of New Zealand Ltd
Publication of EP1169030A1 publication Critical patent/EP1169030A1/fr
Publication of EP1169030A4 publication Critical patent/EP1169030A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • This invention relates to methods and compositions for promoting production gains in animals and for enhancing efficacy of therapeutic agents.
  • Animals are susceptible to both external and internal parasitic infection and disease. This is especially true in an agricultural environment where a high concentration of animals means that infection and reinfection can easily occur.
  • Parasitic and disease loads on livestock are known to be responsible for a number of conditions such as poor growth, anaemia, scouring, indigestion, poor feed conversion, depression and premature death. These conditions hamper meat production and quality and have a detrimental economic impact on both the farmers and the industry in general.
  • therapeutic agents including vaccines, antibiotics, anthelmintics (also known as anthelminthics) and other anti-pathogenic agents have been used to control disease and the numbers of parasites in and on livestock.
  • Therapeutic agents come in a number of forms, including drenches, pour-ons, wipe- ons, injectables, oral dosages or slow release compositions and are used to prevent, control or eliminate internal and external parasites and disease.
  • Therapeutic agents and especially vaccines, antibiotics and anthelmintics are now well recognised as essential to healthy livestock growth.
  • therapeutic agents have disadvantages in that targeted organisms have been found to be developing resistance.
  • One method used to tackle the increase in resistance has been to increase the number of doses and amounts of the agents administered to livestock.
  • US 4,046,890 discloses a pharmacologically active group of benzodiazepine derivatives said to exhibit anthelmintic, anticonvulsant, sedative, and muscle relaxant activity. There is no suggestion that this multiplicity of properties is particularly advantageous, that anthelmintic effectiveness is superior to that of other anthelmintics, nor any suggestion that production gains were achieved using these compounds.
  • Nutritional supplements have been proposed for use in reducing the effects of stress on animals. Examples of such supplements are described in US 5,505,968 and US 4,600,586. US 5,505,968 discloses a supplement comprising a combination of tryptophan, electrolytes, and amino acids. By improving animal nutrition the effects of stress on meat quality degradation, and loss in liveweight are said to be reduced. The composition does not treat stress per se. There is no suggestion to use the composition with therapeutics such as anthelmintics, nor a suggestion that production gains can be achieved with these supplements.
  • US 4,600,586 similarly discloses a method for producing a feed supplement comprising primarily polyethylene glycol and molasses for use in reducing "lot adaptation stress". Minor ingredients are mixed to homogenicity with an effective amount of polyethylene glycol, then added to molasses and remaining polyethylene glycol. It is stated that if not mixed this way, that is, if merely admixed, then the composition is not effective to treat adaptation stress. Reduction in stress is achieved through increased metabolic utilisation of nutrients. The use of anxiolytics ?er se is not taught, the compositions are not suggested as being generically useful to treat stress. There is no suggestion that broad based production gains can be achieved using the nutritional supplement. There is no discussion of the combination of the supplement with anthelmintics or other therapeutic agents.
  • antistress agents when administered to an animal can generate a broad range of production gains in that animal. This property of antistress agents has not previously been recognised. Moreover, the applicants have also found that selected antistress agents, and combinations thereof, when administered to an animal can generate a broad range of production gains in that animal beyond what might be anticipated from reduction in stress alone.
  • An object of the present invention is to provide methods and agents for promoting production gains in animals or at least provide the public with a useful choice.
  • a first aspect of the present invention provides a method for promoting production gain, in an animal, the method comprising administering at least one therapeutic agent to the animal and reducing the stress experienced by the animal.
  • stress experienced by the animal is achieved by reducing physical causes of stress.
  • reduction in stress is achieved by administering an antistress agent to the animal.
  • Animal production gain is preferably a weight gain.
  • the present invention provides a method for enhancing the efficacy of a therapeutic agent, the method comprising the co- administration of at least one therapeutic agent and at least one antistress agent.
  • the present invention provides a therapeutic composition comprising at least one therapeutic agent and at least one antistress agent.
  • the therapeutic composition is formulated as a slow-release composition.
  • the therapeutic composition is an anthelmintic composition.
  • the invention extends to the use of antistress agents as adjuvants for therapeutic agents and compositions.
  • a further aspect of the present invention contemplated is the use of antistress agents as promoters of production gain in animals.
  • the invention provides a method of promoting production gain in an animal, the method comprising administering to said animal at least one antistress agent.
  • the method comprises administering a composition of the invention.
  • the animal is an animal infected with helminths and the therapeutic composition is an anthelmintic composition.
  • the invention also provides a second therapeutic composition comprising a therapeutic agent and a nitric oxide promoter.
  • Figure 1 is a bar graph with a superimposed line graph depicting the level of faecal egg estimates on the bar graph and animal growth on the line graph for chronically stressed animals and a control group.
  • Figure 2 is a line graph depicting the level of faecal egg estimates on the first Y axis and animal growth on the second Y axis line graph for acutely stressed animals and a control group.
  • Figure 3 is a bar graph with a superimposed line graph depicting the level of faecal egg estimates on the bar graph and animal growth on the line graph for chronically stressed animals treated with metyrapone.
  • Figure 4 is a line graph showing the effects of administration of metyrapone on acutely and chronically stressed animals.
  • Figure 5 is a bar graph showing the effect on animal growth of metyrapone.
  • Figure 6(a) is a bar graph which shows the differences in average weight of broiler chickens (+/-SED) relative to control birds in treatment groups exposed to cold stress (28°C temperature during weeks 1 and 2). All groups were removed to 21 °C after 2 weeks. Symbols above columns represent significant differences in weight ( PO.05; + PO.01; * P0.001) from control birds.
  • Figure 6(b) is a bar graph which shows the differences in average weight of broiler chickens (+/-SED) relative to control birds in treatment groups maintained at optimum temperature (32°C) for weeks 1 and 2. All groups were removed to 21 °C after 2 weeks. Symbols above columns represent significant differences in weight ( P ⁇ 0.05; + P ⁇ 0.01; * P0.001) from control birds.
  • Figure 7 is a bar graph which shows percentage differences in average weight of broiler chickens relative to control birds in treatment groups exposed to cold stress (28 °C) during weeks 1 and 2.
  • FIG 8 is a bar graph which shows average Feed Conversion Ratio (FCR) of broiler chickens from treatment groups exposed to cold stress (28 °C) during weeks 1 and 2. Symbols above columns represent significant differences in weight ( ° P ⁇ 0.05; + P ⁇ 0.01) from control birds.
  • FCR Feed Conversion Ratio
  • FIG. 9 is a bar graph which shows the differences in average Feed Conversion Ratio (FCR) of broiler chickens (+/-SED) relative to control birds in treatment groups exposed to cold stress (28 °C) during weeks 1 and 2. Symbols above columns represent significant differences in weight ( ° P ⁇ 0.05; + P ⁇ 0.01) from control birds.
  • FCR Feed Conversion Ratio
  • Figure 10 is a bar graph which shows percentage differences in average weight of pigs relative to low stress control animals and adjusted for initial liveweight, breed and sex, maintained under high and low stress conditions and orally dosed with either three concentrations of anti-stress compound or sugar carrier alone. Bar represents 6 week period when animals were dosed.
  • Figure 11 is a bar graph which shows gain in weight for the first two weeks after weaning in control animals or animals treated with the experimental compound at the highest doses (Formulation A). Mean and standard deviation presented.
  • Figure 12 is a line graph which illustrates species dose response differences to multiple dosing with metyrapone mixtures over time.
  • Gain in efficiency calculates the gain in growth alone against increased costs due to increased feed, the metyrapone and potential increased labour costs for administration compared to non-metyrapone control counterparts. This is expressed as a % gain over these control animals. Mean and standard deviation (sd) presented.
  • Figure 13 is a line graph which illustrates the synergistic effect of vitamin C, isoleucine, leucine and valine on the effects of metyrapone in sheep. Also shows the slight gain from vitamin C, isoleucine, leucine and valine alone without metyrapone.
  • Figure 14 is a line graph which demonstrates an increased gain by the addition of pyrollopyrimidine (mg) to 0.001 g/kg liveweight metyrapone and O.lg vitamin C and 0.005g each of leucine, isoleucine and valine. Mean and standard deviation displayed.
  • Figure 15 is a line graph which illustrates effectiveness of metyrapone alone or in combination in increasing effectiveness of a standard anthelmintic. Mean and standard deviation displayed.
  • Figure 16 is a line graph which illustrates the average number of lambs live born per ewe and average birth liveweight over 3 seasons for control ewes versus ewes previously treated with metyrapone. Mean and standard deviation presented.
  • Figure 17 is a line graph which illustrates the average number of lambs live born per ewe and average birthweight over a season with acute treatments. Mean and standard deviation.
  • Figure 18 is a line graph which illustrates the effects of metyrapone, vitamin C, leucine, isoleucine and valine on liveweight recovery in sheep following surgery under general anaesthesia.
  • Figure 19 is a line graph which illustrates the effects of metyrapone, vitamin C, leucine, isoleucine and valine on liveweight recovery in rats following surgery under general anaesthesia.
  • Figure 20 is a bar graph which illustrates the different stress relieving agents administered to sheep every 2 months with anthelmintics and growth measured over a year. Mean and standard deviation is shown for each treatment group.
  • Figure 21 is a bar graph which illustrates the effect of treatments on % bodyfat in poultry (mean and standard deviation presented).
  • Figure 22 is a line graph which illustrates effectiveness of a nitric oxide donor SNAP in increasing effectiveness of a standard anthelmintic. Mean and standard deviation displayed.
  • antistress agents when administered to animals have unexpected effects in promoting a broad range of production gains in animals and increasing the efficacy of therapeutic agents.
  • Selected antistress agents exhibit particularly surprising properties in promoting production gain and in increasing the efficacy of therapeutic agents.
  • production gains may be surprisingly promoted by administering one or more therapeutic agents to an animal and reducing stress experienced by same.
  • the present invention provides a method for promoting production gain, the method comprising administering at least one therapeutic agent to an animal and reducing stress experienced by the animal.
  • production gain is a broad term encompassing growth rates, increases in body weight, reproductive success, increase in birthweights, production against or recovery from trauma, efficiency of feed conversion, lean tissue mass, and body fat reduction, or combinations thereof. These terms can be read alone or in combination in place of the term "production gain”.
  • Animals susceptible to treatment according to the invention include humans and other animals. Other animals may encompass pets and livestock including cats, dogs, birds, pigs, sheep, fish, mink, deer, goats, cattle, horses, ducks, chickens and turkeys, but are not limited thereto. Best results are likely to be achieved with animals which are prone to high levels of stress.
  • the animals to be treated are sheep, deer, goats, cattle, chickens and pigs.
  • therapeutic agent refers broadly to agents useful in the treatment or prevention of disease or infestation in an animal or otherwise useful in promoting production gain such as animal growth, and well being. Included in the term are vaccines, antibiotics, anthelmintics, other anti-pathogenic agents, growth promoters, performance enhancers, vitamin, amino acid, and mineral supplements, or combinations of these, but are not limited thereto.
  • therapeutic composition is to be similarly understood as broadly defined.
  • performance enhancers is used in the sense that it is employed in the pig and poultry industry to cover antibiotics and oligosaccharides that are primarily prophylactic or therapeutic against disease.
  • Vaccines and antibiotics are described for example in The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs, A. Kucers, S.M. Crowe, M.L. Grayson, J.F. Hoy: 5th Edition Butterworth Heinemann 1997; and Equine Drugs and Vaccines, E. Kelton and T. Tobin, Breakthrough Pub. 1995; and Vaccines for Veterinary Applications, A.R. Peters (Ed.) 1993 all incorporated herein by reference.
  • Anthelmintics are one preferred group of therapeutic agents for use in the present invention.
  • Suitable classes of anthelmintics which can be used include those active against cestodes, trematodes, nematodes and acanthocephala.
  • the compounds may be selected from the group comprising simple heterocyclic compounds, benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates, macrocyclic lactones, arsenicals and anticestodal drugs.
  • suitable anthelmintic compounds are selected from the group comprising piperazine, diethylcarbamazine citrate, thiabendazole, fenbendazole, albendazole, oxfendazole, oxibendazole, febantel, tetramisole (levamisole, levamisole hydrochloride), pyrantel tartrate, pyrantel pamoate, morantel tartrate, dichlorvos, milbemycin oxime, eprinomectin, moxidectin, N-butyl chloride, toluene, hygromycin B, sodium arsenamide sodium, melarsomine, praziquantel, epsiprantel, clorsulon, triclabendazole, diazinon, benzimidazole, salicylamide, isoquinoline and cyromazine amongst others.
  • Preferred commercially available anthelmintics for use in the invention include Fasinex®, Soforen®, Endex®, Combinex®, Parifal®, Neocidol®, Acutak®, Dimpygal®, Nucidol®, Samicida®, Topclip®, Sentinel®, Vetrazin®, Avermectin®, Ivermectin® and Doramectin® but are not limited thereto. Combinations of two, three or more anthelmintics with the same or different anti-pest activity are also contemplated.
  • the therapeutic agents referenced above include drenches, pour-on formulations, injectables, oral dosage forms and slow release formulations, amongst others. It will therefore be appreciated that administration of the therapeutic agent at least orally, parenterally, topically and by injection is contemplated.
  • Single and multiple dosing regimes are contemplated. Multiple dosing regimes may comprise administration of two or more agent doses to different sites on, or by different routes of administration to, an animal at the same time. Oral administration may also be achieved by supplying the agent in animal foodstuffs, or water. In one embodiment, multiple dosing regimes may comprise administration of two or more doses of agents to different sites on an animal over a period of time covering hours, days, weeks or months.
  • animals are dosed every two to four months by a combination of pour-on, injection and oral treatments.
  • For smaller animals or birds administration may be as a feed constituent on a daily, weekly, monthly, bimonthly or longer basis.
  • the applicant has also discovered that a combination of selected vitamins and long branched chain amino acids can exhibit a therapeutic effect.
  • the combination comprises vitamin C with one or more amino acids selected from isoleucine, leucine, and valine, but preferably a combination of all three.
  • the therapeutic effects achieved are an increase in effectiveness of therapeutics such as anthelminthics and increase in production gain such as growth in stressed animals.
  • the combinations have also been shown to increase the effects of antistress agents such as metyrapone.
  • the combinations therefor also exhibit antistress agent properties.
  • Each of the vitamin C and amino acids may be used in dose ranges of from 0.0001 g/kg to 1 g/kg of animal body weight.
  • Dosage rates for vitamin C when used in combination with antistress agents is generally between 0.005 to 0.5 g/kg, preferably 0.01 g/kg to 0.1 g/kg, and most preferably 0.1 g/kg.
  • Dosage rates for the amino acids when similarly used in combination with antistress agents is 0.0001 g/kg, and most preferably 0.001 g/kg to 0.005 g/kg and most preferably 0.005 g/kg.
  • the vitamin C and optimal amino acids may be administered separately, or together in a single composition. Dosage rates for the constituents when used separately can be readily calculated using protocols presented herein.
  • animal's state of stress can contribute to the lasting efficacy of either a pour-on, oral or an injectable agent.
  • Animals that have a high acute level of stress, at the time of application, or alternatively a low to high chronic stress load for some time prior to, or after, application show a lowered efficiency from the dosage and show a quicker re- infestation.
  • the stress undergone by the animal may be psychological stress or physical stress.
  • Psychological stresses include restraint, handling and novelty stress.
  • Physical stresses include hunger, thirst, fatigue, injury, trauma, surgery or thermal extreme stress.
  • the stress may be also be chronic or acute.
  • the stress experienced by the animal may also be characterised as being of short duration or alternatively of long duration.
  • the stress reduction preferably takes place before the administration of the therapeutic agent, but can be after the administration of the agent.
  • the stress reduction is preferably of an order of at least the time between any agent administrations to the animal.
  • stress reduction can be achieved by reducing physical causes of stress, preferably by way of reduced handling of the animals. This can be achieved by reducing intervention with the normal living patterns of the animal. It may include reducing animal (for example dog) and human interaction with the animals, limiting movements, shortening transport procedures and the like. However, physical stress reduction is not always practical.
  • stress reduction is achieved by administering at least one antistress agent to the animal.
  • antistress agent refers to compounds or compositions effective in reducing stress. This may be physiological or psychological stress or a combination thereof. Not included are agents which simply act as nutritional modifiers such as foodstuffs, for example, molasses and propylene glycol, or electrolyte combinations. Accordingly, the antistress agents used herein are not simply nutritional modifiers but are also physiological and or psychological stress reducers er se. Any appropriate antistress compounds or compositions known in the art may be employed. The antistress agent is preferably long-acting, although short acting antistress agents are not excluded. In one embodiment, the antistress agent is formulated as a slow- release composition.
  • Suitable classes of antistress agents including glucocorticoid inhibitors, corticotrophin releasing hormone inhibitors, ACTH inhibitors, cholecystokinin inhibitors, benzodiazepines, gamma amino butyric acid potentiators, anti-glutaminergics and serotonergics amongst others.
  • Preferred classes of antistress agents are pyridyl propanones including metyrapone, antiprogestins including mifepristone (RU 38486), and benzoylamino dipropylamino oxopentanoics including proglumide, and peptides such as astressin, an amino acid peptide. Selection of an antistress agent can be made according to broad criteria such as animal species, age, and types of stress. It is noted that antiprogestins are contradicted for use in pregnant or conceiving animals.
  • Vitamin C and specific amino acid combinations unexpectedly exhibit both therapeutic and antistress properties.
  • Vitamin C alone and combinations with one or more of the amino acids valine, leucine and isoleucine are therefore also classed as anti-stress agents for the purposes of this invention.
  • preferred antistress agents include metyrapone, mifepristone (RU 38486), astressin CRH 9-41, proglumide, diazepam, allopregnanolone, dextromethorphan, zimelidine, vitamin C in combination with valine, leucine and isoleucine, and paroxetine but are not limited thereto.
  • Combinations of two, three or more antistress agents with the same or different activity are also contemplated for use herein.
  • Combinations with vitamin C and one or more of the amino acids valine, leucine and isoleucine are also provided.
  • a preferred combination for nonpregnant and nonconceiving animals includes metyrapone and mifepristone (RU 38486). For pregnant or conceiving animals proglumide or astressin and metyrapone is currently suggested.
  • Astressin is a strong anxiolytic agent and maybe of particular use in high stress situations such as injury, surgery or other trauma.
  • a particularly preferred antistress agent for use in the present invention is metyrapone. This compound acts to suppress some of the physiological and psychological stress responsiveness in an animal, including elevation of levels of glycocorticoid hormone cortisol.
  • Vitamin C combinations increase the effects achieved.
  • Antistress agents may again be administered in a broad effective range. Appropriate dosage rates can be selected by the skilled reader according to known protocols for treating a variety of animals. Variation will occur based on the animal to be dosed, age, body weight and the like as discussed above. Dosages within the range of 0.000001 g/kg to 2 g/kg liveweight of total antistress agent whether a single agent or a combination is used, are feasible.
  • Preferred ranges are 0.0005 to 1 g/kg, 0.001 to 0.1, and most preferably 0.01 to 0.1 g/kg.
  • a preferred dosage range is 0.001 to 0.1 g/kg, preferably 0.01 g/kg liveweight.
  • Dosages within the range may not be suitable for all animals in given circumstances. Animals in different situations may respond differently. As illustrated in Example 8 higher or lower doses of the antistress agent may be appropriate for pigs under stress.
  • the present invention provides a method for enhancing the efficacy of a therapeutic agent, the method comprising the co-administration of at least one therapeutic agent and at least one antistress agent to an animal.
  • the antistress agent is preferably selected from the pyridyl propanone, progestin or peptide group of antistress agents, or is a vitamin C combination. Desirably, the agent is metyrapone.
  • Co-administration encompasses both concurrent and sequential administration.
  • sequential administration it is not critical whether the therapeutic agent or antistress agent is administered first. Sequential administration may occur over a period of minutes, hours, or days. However, concurrent administration is preferred.
  • the therapeutic agent and antistress agent are preferably formulated in the same composition.
  • compositions comprising at least one therapeutic agent and at least one antistress agent.
  • the therapeutic and antistress agent may be selected from any of the therapeutics and antistress agents or combinations thereof referenced above or otherwise known in the art.
  • the compositions are useful for promoting production gains in animals.
  • Selected compositions may additionally exhibit synergistic properties. Foremost among these are compositions including at least one agent selected from vitamin C combinations and the progestin, peptide or pyridyl propanone group of antistress agents.
  • the therapeutic agent is an anthelmintic.
  • the anthelmintic is selected from Ivomec, Endex and levamisole and the antistress agent is metyrapone.
  • a further preferred composition also includes a non-vitamin C antistress agent and vitamin C, one or more of the amino acids selected from valine, leucine and isoleucine, or a combination thereof as discussed above.
  • a non-vitamin C antistress agent selected from valine, leucine and isoleucine, or a combination thereof as discussed above.
  • the addition of this vitamin and amino acids, or combination further enhances the effect of the antistress agent.
  • the amounts of therapeutic agent(s) and antistress agent(s) in the composition may vary within a broad range, so long as effectiveness is maintained.
  • Antistress agent(s) will generally be present in individual or combined form between 0.0001 to 99.999% of the composition. Suitable concentrations can be calculated based on the weight/kg of liveweight dosage information given above. For best results across species tested to date, it is suggested that between 0.01 and 0.0001 g/kg be used together with 0.1-0.001 g/kg of vitamin C, and 0.005 g of each of valine, isoleucine and leucine.
  • compositions of the invention can be formulated for oral, parenteral and topical administration or for injection.
  • the therapeutic compositions of the invention may further contain pharmaceutically or agriculturally acceptable carriers, diluents, excipients, disintegrators, stabilisers, and binding agents and such other materials as are known in the art and customarily employed in such formulations.
  • the compositions may further comprise preservatives, antioxidants, colourants, feedstuffs, nutrients, vitamins, lubricants, salts, lipid membrane transfer facilitators, other therapeutic agents and nitric oxide promoters discussed later herein. This list is illustrative rather than exhaustive of the components of the composition. Suitable substances are well known in the art, for example in Pitha et al 1986; Amorphous water soluble derivatives of cyclodextrins: nontoxic enhancing excipients. J. Pharm Sci 74 (9) 987.
  • compositions further including a lipid membrane transfer facilitator are therefore contemplated.
  • Facilitators know in the art include pyrolidones such as N- methylpyrolidone, and pyrimidines such as pyrollopyrimidine, amongst others.
  • Preferred facilitators are pyrollopyrimidine and U-101033E (Also see Andreous P et al. J. Neuro Science Res., 47: 650-654 and Hall E et al 1995 Acta NeuroChir 66: 107- 113 incorporated herein by reference).
  • the concentration of the facilitator may be from 0.0000001 to 10% of the antistress agent component, preferably 0.01 to 0.1%
  • Performance enhancers are a group of therapeutic agents including antibiotics and muccan oligosaccharides. They are of particular importance in the pig and poultry industry.
  • An example of such an enhancer for use is Avilamycin at a concentration of between 0.01 to 0.5 g/kg, preferably 0.2 g/kg.
  • Bio-Mos (Alltech Inc, Kentucky, USA) is an example of a muccan oligosaccharide.
  • An appropriate range for the oligosaccharides is from 0.01 g/kg to 5 g/kg of liveweight, preferably 1 g/kg.
  • Solubilisers can be important components for solubility in aqueous solutions, and should be non-toxic. Many suitable solubilisers are known in the art. An example of a preferred solubiliser that may be used is 2-hydroxoypropyl-beta-cyclodextrin from 1 to 45% of the solution.
  • a typical composition for delivery could consist of 0.001% metyrapone, 0.01 % vitamin C, 0.0005% each valine, isoleucine and leucine, 0.0001% pyrollopyrimidine, 5% glucose, 0.1% sodium benzoate and the remainder up to a IL or 1 kg total coming from a carrier fluid or feed.
  • the composition is formulated as a slow-release composition, such as are known in the art.
  • Slow release of the composition may conveniently be achieved through the use of boluses or time release capsules.
  • boluses contemplated by the invention are those as set out, for example in GB 2, 122,086, US 3,535,419 and US 5,720,972, which are incorporated herein by reference.
  • selected antistress agents especially those from the pyridyl propanone group when combined with therapeutic agents or compositions increase the efficacy of the therapeutic agent beyond what would be expected for the agents acting alone. Efficacy is usefully measured either in terms of increased effectiveness or duration of effectiveness of therapeutic agent.
  • the route of action may vary.
  • the antistress agent may act to increase the antibody titre and hence effectiveness.
  • a still further benefit is reduction in sfress at any stage in an animal's life, including in a pen prior to slaughter, where stress can reduce overall meat yield and quality.
  • compositions and methods of the invention employing a therapeutic agent and an antistress agent all exhibit a significant benefit in promoting production gains, especially animal growth (e.g. weight gain), reproductive success and improved lean tissue to fat ratios.
  • Animal growth may comprise growth overall during the course of the animal's life or in a pen prior to slaughter.
  • Animal growth in the context of the present invention is primarily measured in terms of weight gain, although other measures are not excluded.
  • the invention provides a method of promoting production gain in an animal, the method comprising administering to said animal at least one antisfress agent.
  • the present invention also provides the use of antistress agents as discussed above as production gain promoters.
  • the use may be in the preparation of a composition for use as a production gain promoter in animals.
  • the compositions may range from feedstuffs to any of the therapeutic compositions discussed above.
  • the antistress agents to be administered comprise any of those agents or compositions referenced above. Administration dosage levels and protocols are similarly discussed above.
  • the antistress agents may be used in animal feedstuffs to achieve the growth promotion benefits.
  • suitable feedstuffs include hay, silage, haylage, grain, cereals and chicory or any other animal feedstuff produced naturally or artificially manufactured.
  • One of the production gains identified above is the protection against or recovery from trauma.
  • antistress agents as protective or recovery aiding agents before, during or after periods of physiological or physical stress as discussed above is specifically contemplated.
  • the use of antistress agents in conjunction with surgery, injury or trauma may be desirable. Examples of trauma include myocardial infarction and cerebrovascular accidents (strokes and brain haemorrhage) but are not limited thereto. That is, the antistress agent may have protective function, especially an organ protective function in the case of physical or psychological stress. Recovery may be conveniently measured through liveweight loss or gain subsequent to injury, surgery or trauma. Animals treated with antistress agents before surgery generally demonstrated no loss in weight, or positive gains compared with weight losses in animals not so treated.
  • Methods of treating an animal to prevent or aid recovery from stress, particularly surgery or trauma comprising administering one or more antistress agents alone, or with one or more other therapeutic agents or compositions is therefore contemplated.
  • the present invention also extends to the use of antistress agents as adjuvants for therapeutic agents.
  • the use may comprise the concurrent or sequential administration of one or more antistress agents with the therapeutic agent(s). Suitable agents and administration protocols are as discussed above.
  • antistress agents may also be in the preparation of a composition for use in animal treatment.
  • examples of such compositions include drenches, vaccines, anthelmintics and the like as discussed above.
  • the invention provides a method of treating an animal, the method comprising administering a therapeutic composition of the invention to said animal.
  • the animal is an animal infected with helminths and the therapeutic composition is an anthelmintic composition.
  • the therapeutic composition is an anthelmintic composition.
  • any of the compositions and administration regimes referenced above may be employed in this method of the invention.
  • the applicant has also discovered that the effectiveness of therapeutic agents, especially anthelmintics can be enhanced through the use of substances which increase nitric oxide levels. The applicants hypothesised that the effectiveness of the antistress agents was in allowing natural (endogenous) nitric oxide to facilitate anthelmintic treatment.
  • nitric oxide can reduce gut parasite numbers. It seems very likely that this effect occurs via an inflammatory process briefly making the gut wall inhospitable to infestation. Cortisol, the stress hormone, counteracts the effects of nitric oxide and other inflammatory mechanisms.
  • a second route for the generation of immune response to parasites may involve the liberation of certain long chain amino acids from muscle tissue. This amino acid liberation is a known trigger for immune response, and humans with muscular atrophy or high levels of stress are poor at such mobilisation. Acute or chronic stress in animals may thus suppress both this muscle origin and nitric oxide generated immune response and in doing so reduce their synergistic efficiency in decreasing parasite numbers.
  • the invention provides a second therapeutic composition comprising a therapeutic agent and a nitric oxide promoter.
  • the therapeutic agents include any of the agents discussed above.
  • the nitric oxide promoter may be selected from groups known in the art including L-arginine, diethylamine nitric oxide complex, sodium nitroprusside and S-nitroso-N- acetylpenicillamine amongst others. Appropriate dosage rates range from 0.00001 g/kg livewight to 0.01 g/kg. A preferred range is from 0.0005 to 0.0005 g/kg, preferably 0.0001 g/kg.
  • the compositions may be formulated and administered as discussed above for the first therapeutic composition.
  • a method of treating an animal using this second therapeutic composition by administering same also forms part of the invention.
  • antistress compounds with their potential to promote a broad range of production gains have clear utility in farming, pet care, zoos and animal based industries generally. Major economic and welfare implications are also apparent.
  • antistress compounds with performance enhancers, vitamin C and amino acids or combinations thereof can improve production gains and therefore economic returns to farmers.
  • sheep were divided into pairs from initial twins. All the animals were grazed together, on the same paddocks, from pairing through to the end of the trial. They were thus exposed to the same potential parasite load and the same access to feed and water. The animals were also genetically similar (i.e at least one shared parent). Experiments were begun when the animal was 3 months of age.
  • the other half of the pairings (chronic stress group) were exposed to the same handling three times a week (consistent with the single weekly procedure above) and in addition to this were run around a paddock by either a human or dog (alternating) for 10 minutes. In this manner a mild, chronic, handling stress was imposed on these animals. Races and handling facilities were cleaned between animal movements to avoid any risk of parasitic contamination.
  • Animals were subject to the same anthelmintic treatments consisting of three pour-on (Ivomec pour on, MSD 1 ml per 50kg), three oral (Endex, Novartis - 1ml per 5kg) and three injectable treatments (levamisole. 7.5 mg/kg) per year (every four months).
  • the animals in the chronic stress group also all received a chemical substance metyrapone (in an oral form at 5mg/kg live weight) at the time of anthelmintic treatment.
  • metyrapone in an oral form at 5mg/kg live weight
  • This substance is known to suppresses some of the physiological stress responsiveness, including elevation of levels of the glucocorticoid hormone cortisol.
  • Chicks were assigned at random to one of 12 groups:
  • SAC Agent (2-methyl-l, 2-di-3-pyridyl-l -propanone, vitamin C, valine, isoleucine and leucine mixture), mixed with a glucose-based polymer carrier (0.0 lg drug to lg of carrier) before addition to the feed in the following doses.
  • the SAC increased growth rates in broiler chickens exposed to cold stress.
  • Birds receiving Formulation A were 22.9g (12.9%) heavier than control birds after 1 week of cold stress (PO.001), 53.7g (11.2%) heavier at the end of the cold stress period (week 2; P ⁇ 0.001), and 89.3g (9.5%) heavier after 3 weeks of the trial (PO.001).
  • the weights of birds receiving the antibiotic performance enhancer were not significantly different (P>0.05) to control birds during the period of cold stress (week 1: 3.5g (2.0%): week 2: 6.3g (1.3%)). However, when the stressor was removed, the birds showed a significant (PO.01) increase in weight relative to control birds (week 3: 42.6g (4.5%)), although the effect was not maintained during the remainder of the trial (week 4: 35.2g (2.2%).
  • Treatment with a combination of Formulation A of the SAC and performance enhancer or oligosaccharide increased the efficiency with which the feed was utilised for weight gain Feed Conversation Ratio (FCR).
  • FCR Feed Conversation Ratio
  • broiler chickens kept at sub-optimal temperatures (cold stressed) and given the SAC approach, and even surpass, the efficiency of feed conversion to weight gain observed in control birds at optimum temperatures (1.078 vs 1.068 after 1 week of cold sfress: 1.930 vs 2.071 week 2).
  • Groups of 3 animals were housed per pen on weaner flat decks maintained at 28-30°C. Each group had access to a commercial-type grower meal and mineral/vitamin supplement (Tasmix pig grower vitamin mineral premix: Tasmax Vaccines Ltd, Auckland, New Zealand), in excess of daily requirements from a hopper placed in each pen. Daily feed intakes were recorded for each group of animals and water was freely available.
  • Groups 1 and 3 Low level stress associated with normal daily cleaning and feeding and weekly weighing.
  • Groups 2, 4, 5, and 6 Additional stress imposed on the animals by mixing each group twice weekly. One animal from each of the three groups comprising each treatment was interchanged immediately after weighing.
  • the SAC (2-methyl-l, 2-di-3-pyridyl-l -propanone, vitamin C, valine, isoleucine and leucine mixture) was mixed with a glucose-based polymer carrier (O.Olg drug to lg of carrier), before being dissolved to give the following doses.
  • Formulation A per kg bodyweight: 0.5mg 2-methyl-l, 2-di-3-pyridyl-l -propanone 5mg Vitamin C 5mg Valine, isoleucine and leucine
  • Piglets freated with Formulations A and C continued to show increased weight gains and reached goal weights faster compared to control and animals freated with dose B during the course of the mild stress experiment.
  • FIGS 10 and 11 display this data.
  • vitamin C isoleucine, leucine and valine
  • Metyrapone alone also increased growth, except in animals that were deprived of vitamin C and long chain branched amino acids (data not shown).
  • Vitamin C, isoleucine, leucine and valine had a small growth promotant effect in mildly nutritional deprived animals. It is possible that a certain level of these amino acids and vitamin C are needed for metyrapone to have its maximal effect.
  • a synergistic growth promotant effect of a mix of vitamin C, isoleucine, leucine and valine is thus suggested. Proportional mixture of these compounds seems important, with the most successful mixture being one of approximately: 0.1 g vitamin C and 0.005g each of valine, isoleucine and leucine to each O.Olg of metyrapone.
  • Figure 13 demonstrates the increased gain in metyrapone effect from the addition of a range of dosages of vitamin c, isoleucine, leucine and valine. It also demonstrates a small gain from these compounds alone.
  • Pyrollopyrimidine is known in art as a lipid transfer facilitator and it is hypothesised that addition of this compound increased the amount of effective dose of metyrapone, vitamin C, isoleucine, leucine and valine crossing cell membranes.
  • Figure 17 illustrates this result.
  • Figure 20 illustrates the results obtained.
  • a O.OOOlg/kg mifepristone (RU 38486) dose alone had no effect compared to control but when added to metyrapone increased significantly the effectiveness of that dose of metyrapone, a synergistic effect.
  • Table 1 The data is usefully summarised in Table 1 below. Table 1. Dose related effects of mifepristone (RU 38486) or astressin on metyrapone growth increasing properties.
  • Samples vary greatly in fat content. Repeatedly washing the sample with petroleum ether by refluxing in a Soxtec apparatus dissolves the fat. The solubilised fat is then collected in the distillation cup and the increase in the weight of the cup represents the dissolved fat.
  • Sample boats made by folding aluminium foil into boats approximately 10cm x 10cm square, wipe with acetone and labelled with sample number on the outside of the foil. Disposable gloves worn when handling meat samples and boats.
  • sheep received standard anthelmintic treatments similar to experiments 3 and 4, with anthelmintics and treatments given every four months.
  • Treatment in 10 of these animals consisted of the anthelmintic dosing and S-nitroso -N-acetylpenicillamine, a nitric oxide donor at a dose of 0.000 lg per kg liveweight in an oral form.
  • the other 10 received the anthelmintic and a glucose control.
  • Figure 22 illustrates this.

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Abstract

La présente invention concerne des compositions et des procédés permettant de favoriser des gains de production animale et de renforcer l'efficacité d'agents thérapeutiques. Ces gains s'obtiennent par une réduction du stress, y-compris par l'administration d'agents antistress. L'invention concerne également des agents thérapeutiques tels que des agents anthelminthiques et antistress.
EP00911506A 1999-03-12 2000-03-13 Agents et procedes permettant de favoriser des gains de production animale Withdrawn EP1169030A4 (fr)

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NZ334627A NZ334627A (en) 1999-03-12 1999-03-12 A therapeutic composition containing a therapeutic agent such as an anthelmintic and an antistress agent such as metyrapone or a nitric oxide promoter for increasing efficacy of therapeutic agents and animal growth
NZ33462799 1999-03-12
PCT/NZ2000/000026 WO2000054766A1 (fr) 1999-03-12 2000-03-13 Agents et procedes permettant de favoriser des gains de production animale

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EP1948238B1 (fr) * 2005-11-10 2013-08-28 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions et procédés pour le traitement de l'addiction et d'autres troubles neuropsychiatriques
CA2646460C (fr) * 2006-03-21 2013-01-22 Taminco Traitement de volaille pour ameliorer le taux de conversion d'aliments ou pour reduire l'incidence de l'ascite
WO2008046576A1 (fr) * 2006-10-16 2008-04-24 Transgene S.A. Utilisation d'antagonistes de glucocorticoïdes en vaccination
GB2503396A (en) * 2008-11-07 2013-12-25 Univ Sheffield Treatment of subclinical Cushing's syndrome and/or incidentaloma
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CA2367444A1 (fr) 2000-09-21
WO2000054766A1 (fr) 2000-09-21

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